PROJECT SUMMARY/ABSTRACT - PROJECT 3 Anti-DNA, anti-N-methyl-D-aspartate receptor (NMDAR) antibodies, denoted DNRAbs, are present in serum of 30 to 40% patients with systemic lupus (SLE). We have explored the pathogenic potential of these antibodies in protected regions of the brain, specifically the hippocampus and the amygdala and have demonstrated that the antibodies enhance NMDAR activation. Based on new data showing that both patients and mice with DNRAbs have higher serum prolactin levels, we now propose that DNRAbs augment the known NMDAR-mediated release of prolactin by pituitary cells that reside outside the protection of the blood-brain barrier. We will determine whether decoy antigens can neutralize DNRAbs leading to a reduction in serum prolactin levels and a decrease in prolactin-induced autoreactivity. These studies are highly relevant to SLE pathogenesis as prolactin has been shown by us and others to abrogate a B cell tolerance checkpoint that is present as B cells develop from the transitional to the mature nave stage and thus to immunocompetence. If our hypothesis is correct, neutralizing DNRAbs will reduce prolactin and diminish pathogenic autoreactivity. The studies are performed in mice but will provide the rationale and the methodology for a clinical trial in patients.